12.7 Organic Synthesis Strategy, Protecting Groups, Rearrangements, and Pericyclic Reactions

12.7 Organic Synthesis Strategy, Protecting Groups, Rearrangements, and Pericyclic Reactions

Quick Answer: Synthesis is a 10-item Organic area. Rearrangement is one of the five reaction types in the 25-item reaction area, and mechanisms add 15 more items. Plan syntheses backward (retrosynthesis), choose the correct order for aromatic substitutions, protect groups that would interfere, and recognize classic rearrangements and pericyclic reactions with their stereochemical rules.

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Retrosynthetic Analysis

E. J. Corey's approach (Nobel Prize 1990) works backward:

1. Disconnect a bond in the target to give idealized fragments called synthons (for example, a carbanion and a carbocation).
2. Replace each synthon with a real synthetic equivalent: a $CH_3^-$ synthon becomes $CH_3MgBr$, and an $R^+$ synthon becomes $R{-}Br$.
3. Use functional group interconversion (FGI) when the needed group must be revealed later, for example making an amine from a nitrile or a ketone from an alcohol.
4. Repeat until you reach available starting materials.

Example: 2-phenylbutan-2-ol can be disconnected three ways at the carbinol carbon: $PhMgBr$ + butan-2-one, $CH_3CH_2MgBr$ + acetophenone, or $CH_3MgBr$ + propiophenone. All three Grignard routes are valid; choose by cost and availability.

Umpolung (polarity reversal) supplies "unnatural" synthons. A 1,3-dithiane, deprotonated by butyllithium, acts as an acyl anion equivalent; hydrolysis afterwards reveals the carbonyl.

Key Carbon-Carbon Bond-Forming Reactions

Ordering Aromatic Substitutions

Directing effects decide the order of steps:

• 3-bromoaniline from benzene: nitrate (the $NO_2$ group is a meta director), brominate (meta), then reduce $NO_2$ to $NH_2$.
• 4-bromoaniline from benzene: nitrate, reduce to aniline, acetylate (moderating the activation), brominate (para), then hydrolyse the amide.

Yield and Strategy

The overall yield of a linear sequence is the product of the step yields: $0.80^5 = 0.33$, or 33% over five steps. Convergent syntheses make fragments separately and join them late, keeping the longest linear sequence short.

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Protecting Groups

Orthogonal protection uses groups removed under different conditions, so one can be removed while the others stay. Peptide synthesis uses this with acid-labile Boc and base-labile Fmoc.

Example: To add $CH_3MgBr$ to the ester of ethyl 4-oxopentanoate without touching the ketone, first convert the ketone to its ethylene ketal. Then add the Grignard reagent and remove the ketal with aqueous acid.

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Rearrangements

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Pericyclic Reactions

Pericyclic reactions are concerted and pass through a cyclic transition state. Woodward and Hoffmann (Hoffmann shared the 1981 Nobel Prize with Fukui) explained their stereochemistry by conservation of orbital symmetry.

The Diels-Alder Reaction ([4+2])

• The diene must adopt the s-cis conformation; cyclopentadiene is locked s-cis and very reactive.
• Electron-withdrawing groups on the dienophile ($C{=}O$, $CN$) speed the reaction.
• It is stereospecific and suprafacial on both components: a cis dienophile gives cis substituents in the product, so dimethyl maleate gives the cis diester.
• The endo rule: the kinetic product has the dienophile's substituents tucked under the diene (secondary orbital overlap).

Woodward-Hoffmann Selection Rules

Example: Heating cis-3,4-dimethylcyclobutene opens the ring by conrotation to $(2E,4Z)$-hexa-2,4-diene, while the trans isomer gives $(2E,4E)$-hexa-2,4-diene.